DAT-Regulation of Nucleus Accumbens Microcircuitry by Oxycodone Exposure and Withdrawal

羟考酮暴露和撤回对伏核微电路的 DAT 调节

• 批准号: 10453673
• 负责人: Patrick Rothwell
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453673
• 关键词: Acute; Analgesics; Behavior; Brain; Brain region; Cells; Chronic; Clinical; Consumption; Data; Dopamine Receptor; Exhibits; Goals; Helping to End Addiction Long-term; Hour; Human; Individual; Infusion procedures; Interneurons; Knowledge; Measures; Mediating; Methods; Modeling; Monitor; Naloxone; National Institute of Drug Abuse; Nature; Negative Reinforcements; Neuronal Plasticity; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Antagonist; Output; Oxycodone; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Procedures; Property; Publishing; Pump; Regulation; Relapse; Reporting; Research; Research Project Grants; Rewards; Role; Side; Slice; Source; Stimulant; Synapses; Synaptic Transmission; United States National Institutes of Health; Withdrawal; addiction; base; clinically relevant; controlled release; drug action; experience; experimental study; gamma-Aminobutyric Acid; in vivo; interest; mu opioid receptors; neural circuit; new therapeutic target; novel; opioid abuse; opioid epidemic; opioid exposure; opioid injection; opioid withdrawal; osmotic minipump; patch clamp; prescription drug abuse; prescription opioid; prevent; programs; synaptic inhibition

DAT18-07: The aversive nature of withdrawal represents a powerful source of negative reinforcement, perpetuating the use and abuse of oxycodone and other prescription opioids. More effective strategies to relieve and prevent withdrawal may decrease consumption of prescription opioids, and facilitate efforts to discontinue use and prevent relapse. These strategies must be informed by a deeper understanding of the neural circuits mediating aversion and other facets of prescription opioid withdrawal. The long-term goal of our research is to determine how opioid exposure and withdrawal modify nucleus accumbens inhibitory microcircuits, and ultimately use this knowledge to reverse or prevent maladaptive changes that contribute to addiction. The nucleus accumbens is commonly associated with reward but also has a “dark side”, contributing to the aversive aspects of opioid withdrawal and other states of aversion. The specific goals of this proposal are to evaluate the contribution of nucleus accumbens fast-spiking interneurons (FSIs) and medium spiny neurons (MSNs) to aversive behavior during oxycodone withdrawal, and determine how oxycodone withdrawal modifies cellular properties of FSIs and MSNs. The scientific premise for this proposal is based on published and preliminary data that nucleus accumbens FSIs and D2-MSNs are activated during opioid withdrawal and regulate aversive states. Our central hypothesis is that FSIs are inhibited by opioid exposure and exhibit rebound activation during opioid withdrawal, modulating aversion through their GABAergic synapses onto MSNs. We predict that chronic oxycodone exposure reorganizes synaptic output of FSIs onto MSNs, changing how FSIs regulate aversion. In AIM 1, we will determine how FSIs, D2-MSNs, and D1-MSNs regulate aversion during oxycodone withdrawal. Using a clinically relevant model of spontaneous oxycodone withdrawal, we will use chemogenetic methods to manipulate the activity of FSIs and MSNs, and measure conditioned place aversion as well as classic somatic signs of withdrawal. We will also determine how FSI manipulations regulate the activation of MSNs. We predict that FSI activation constrains the expression of oxycodone withdrawal through an inhibitory influence on D2-MSNs. In AIM 2, we will determine how the cellular properties of FSIs and MSNs are altered by oxycodone withdrawal. After continuous oxycodone exposure for one week, we will prepare acute brain slices in the presence of oxycodone, and precipitate withdrawal ex vivo by exposing the brain slice to naloxone. We expect to find an increase of GABA release from FSIs onto D2-MSNs during withdrawal, a neuroplastic change that would explain why FSIs constrain aversion during withdrawal. We will also measure the trajectory of cellular changes after repeated withdrawals in vivo, and predict the cyclical engagement of FSIs and MSNs during each withdrawal episode will generate enduring and maladaptive neuroplasticity in the nucleus accumbens. Successful completion of these experiments will uncover a novel role for nucleus accumbens FSIs in opioid effects, and indicate these cells represent a new therapeutic target for alleviating states of opioid withdrawal.

DAT 18 -07：退缩的厌恶性是消极强化的一个强大来源， 继续使用和滥用羟考酮和其他处方类阿片。更有效的战略，以减轻 和防止戒断可能会减少处方阿片类药物的消费，并促进努力停止 使用和预防复发。这些策略必须通过对神经回路的更深入理解来提供信息 调解厌恶和处方阿片类药物戒断的其他方面。我们研究的长期目标是 确定阿片类药物暴露和戒断如何改变丘脑核抑制性微电路， 最终利用这些知识来逆转或防止导致成瘾的适应不良的变化。的 丘脑核通常与奖赏有关，但也有“黑暗的一面”，有助于厌恶 阿片类药物戒断和其他厌恶状态的方面。本提案的具体目标是评估 伏隔核快峰中间神经元（FSI）和中型棘神经元（MSN）对 羟考酮戒断期间的厌恶行为，并确定羟考酮戒断如何改变细胞 FSI和MSN的属性。这一提议的科学前提是基于已公布的和初步的数据 在阿片类药物戒断过程中，丘脑核FSI和D2-MSNs被激活，并调节厌恶状态。 我们的中心假设是，FSI受到阿片类药物暴露的抑制，并在阿片类药物暴露期间表现出反弹激活。 戒断，通过GABA能突触调节MSNs上的厌恶。我们预测， 羟考酮暴露将FSI的突触输出重组到MSN上，改变FSI如何调节厌恶。在 目的1，我们将确定FSI，D2-MSNs和D1-MSNs如何调节羟考酮给药期间的厌恶 戒断使用临床相关的自发羟考酮戒断模型，我们将使用化学遗传学 方法来操纵FSI和MSNs的活动，并测量条件性位置厌恶以及经典的 有戒断症状我们还将确定FSI操作如何调节MSNs的激活。我们 预测FSI激活通过抑制对羟考酮戒断的影响来限制羟考酮戒断的表达。 D2-MSN。在AIM 2中，我们将确定FSI和MSNs的细胞特性是如何被改变的。 羟考酮戒断在连续暴露羟考酮一周后，我们将制备急性脑切片 在羟考酮的存在下，并通过将脑切片暴露于纳洛酮来离体沉淀戒断。我们 在戒断过程中，FSI向D2-MSNs释放的GABA增加，这是一种神经可塑性变化 这就解释了为什么金融稳定机构在退出时会抑制厌恶情绪。我们还将测量细胞的运动轨迹 在体内反复撤药后的变化，并预测FSI和MSNs在每次撤药后的周期性参与。 戒断发作会在延髓核产生持久的、适应不良的神经可塑性。 这些实验的成功完成将揭示一个新的作用，核神经元FSI在阿片类药物 效果，并表明这些细胞代表了缓解阿片类药物戒断状态的新治疗靶点。